Fragile X syndrome is the most common inherited form of mental retardation, affecting about 1 in every 4000 boys and about 1 in every 8000 girls.
Fragile X syndrome (FXS) is a genetic disorder caused by the expansion of a CGG trinucleotide repeat in the 5′ untranslated region (5′-UTR) of the Fragile X mental retardation 1 (FMR1) gene, which is located on the X chromosome. The mutation results in a reduced or absent expression of the Fragile X mental retardation protein (FRMP). Even if the exact function of FRMP is not known, experimental evidences have shown that its normal expression is required for normal neural development.
Depending at least in part on the length of the CGG repeat expansion, FXS patients will present various degrees of symptoms severity. Major symptoms associated with FXS are mental retardation and learning disabilities, in particular delays in learning how to sit, walk and talk. As a consequence, FXS patients usually present nervous or cluttered speech. Moreover, FXS patients may have deficient central executive, working, phonological and/or visual-spatial memories; or difficulty with face encoding.
Behavioral and emotional problems may also be encountered, such as, for example, hyperactivity, stereotypy, anxiety, seizures, impaired social behavior, cognitive delay, irritability, aggression or self-injurious behavior. Moreover, FXS may also cause ophthalmologic problems including strabismus, and recurrent otitis media and sinusitis during early childhood.
Due to the high prevalence of Fragile X syndrome, there is a real need for a specific treatment.
The patent application EP 2 433 635 describes the use of PAK (p21-activated kinases) modulators for treating Fragile X syndrome.
The patent application WO2012/019990 describes the use of glutamate 5 receptor (mGlu5) antagonists for the treatment of Fragile X syndrome.
The patent application AU 2011 236093 describes the use of a gamma-aminobutyric acid agonist, in particular of Baclofen, for treating Fragile X syndrome. The drug STX209, a baclofen derivative, is currently under clinical trial for determining its efficacy, safety, and tolerability for the treatment of social withdrawal in adolescents and adults with Fragile X syndrome.
Other clinical trials are currently in progress, such as, for example, with AFQ056 (a mGluR5 antagonist developed by Novartis), minocycline hydrochloride (an antibiotic which may lower matrix metalloproteinase 9 (MMP9) levels) or Acamprosate (an agonist of a GABA receptor).
However, to the Applicant knowledge, there is currently no drug treatment with prove efficacy for Fragile X syndrome.
The Applicant surprisingly showed that the intracellular chloride level was significantly increased in a mouse model of FXS as compared to the wild-type situation, leading to an abnormal neuronal activity (see Examples). This was surprising as Adusei et al (2010 Neuropharmacology 59:167-171) disclose that the chloride transporters NKCC1 and KCC2 are not involved in FXS.
The present invention thus relates to the use of a modulator of intracellular chloride levels, in particular inhibitor of NKCC or activator of KCC, for treating FXS in a subject in need thereof.